While much research regarding the treatment of schizophrenia has focused on new pharmaceutical compounds, a major correctable cause for treatment resistance remains nonadherence with prescribed medication (Fenton et al. Schizophr. Bull. 1997 23(4):637-51; Kane, J. J. Clin. Psychopharmacol. 1985 5(3 Suppl):22s-27s). Approximately 50% of patients with schizophrenia and other chronic psychotic conditions are believed to be poorly adherent with prescribed medication (Young et al. Bull. Am. Acad. Psychiatry Law 1986 14(2):105-22). A controlled study to measure adherence with a detectable marker reported that 80% of patients with schizophrenia do not take medications as prescribed (Kapur et al. Schizophr. Res. 1991 6(1):49-53). Studies of relapsed patients have reported only 30% to meet the criteria for good adherence in the months prior to admission (Bergen et al. Aust. N Z J. Psychiatry 1998 32(6):815-22; Razali et al. Acta Psychiatr. Scand. 1995 91(5):331-5).
Therapeutic failure secondary to nonadherence often results in deterioration in social function and more intensive interventions including rehospitalization, such that nonadherence was the most important predictor of rehospitalization in a state hospital population (Casper, E. S. and Regan, J. R. Can. J. Psychiatry 1993 38(10):657-61). Furthermore, length of stay upon rehospitalization is shorter among medication adherent patients and they are less likely to require involuntary admission (McEvoy et al. J. Nerv. Ment. Dis. 1984 172(7):412-6). Without antipsychotic treatment, 75% of patients with schizophrenia relapse within one year of first presentation, compared to 15% of treated patients (Ayuso-Gutierrez, J. L and del Rio Vega, J. M. Schizophr. Res. 1997 28(2-3):199-206; Davis, J. M. and Andriukaitis, S. J. Clin. Psychopharmacol. 1986 6(1 Suppl):2S-10S). Discontinuation of antipsychotic medication also has been disclosed to increase risk of relapse approximately 5-fold (Robinson et al. Arch. Gen. Psychiatry 1999 56(3):241-7). Similarly, a study that followed first episode patients for 2 years found relapse rates up to 90% for non-medicated patients (Ram et al. Schizophr. Bull. 1992 18:185-207). Furthermore, good adherence following discharge from the hospital can reduce recidivism from 73% to 27% within one year (Gaebel, W. and Pietzeker, A. Pharmacopsychiatry 1985 18(3):235-9).
Consequences of medication nonadherence can extend beyond the health of the patient. While the majority of people with schizophrenia do not engage in violent behavior, a subset of patients display aggression during periods of psychosis (Casper, E. S. and Regan, J. R. Can. J. Psychiatry 1993 38(10):657-61; Lindqvist, P. and Allebeck, P. Br. J. Psychiatry 1990 157:345-50; Mitchell, E. W. Med. Sci. Law 1999 39(1):23-30; Tam et al. Psychiatr. Serv. 1996 47(1):86-8).
Efforts to increase medication adherence have incorporated behavioral and psychoeducational programs, family interventions and intensive supportive services (Agarwal et al. Int. J. Soc. Psychiatry 1998 44(2):92-106; Amador, X. F. and Gorman, J. M. Psychiatric. Clin. North Am. 1998 21(1):27-42; Bustillo et al. Harv. Rev. Psychiatry 1999 6(5):229-40; Yong et al. Bull Am. Acad. Psychiatry Law 1986 14(2):105-22).
Pharmacological approaches to improved adherence include improving tolerability and efficacy of antipsychotic medication (Bustillo et al. Harv. Rev. Psychiatry 1999 6(5):229-40; Kane, J. Br. J. Psychiatry Suppl. 1999 37:26-9; Kasper, S. Int. Clin. Psychopharmacol. 1998 13 Suppl 3:S71-7; Mauskopf et al. J. Clin. Psychiatry 1999 60(Suppl 19):14-9) through development of new agents and administration of monthly depot preparations of existing agents.
Decreased rates of discontinuation were reported for a newer agent, olanzapine, than an older one (haloperidol) (Tran et al. J. Clin. Psychiatry 1997 June 58(5):205-11; Tran et al. J. Clin. Psychiatry 1997 June 58(6):275). However, newer agents have been reported to have additional side effects including weight gain, sedation, drooling, Q-T prolongation and agranulocytosis (Campbell et al. Br. J. Clin. Pharmacol. 1999 47(1):13-22; Wetterling, T. and Mussigbrodt, H. E. J. Clin. Psychopharmacol. 1999 19(4):316-21).
Monthly depot preparations have been reported as an effective means to decrease relapse and rehospitalization (Gerlach, J. Int. Clin. Psychopharmacol. 1995 9 Suppl 5:17-20). Treatment for noncompliant patients with depot formulations (Haldol-decanoate) is much less expensive per year than oral preparations of newer neuroleptics (risperidone; Galzer, W. M. and Ereshefsky, L. J. Clin. Psychiatry 1996 57(8):337-45). However, a 7-year study of depot medication found a significant number of patients fail to comply with monthly injections and discontinuation linked to relapse (Curson et al. Br. J. of Psychiatry 1985 146:469-74). Therefore, while depot medication improves adherence initially, many patients still become nonadherent (Weiden et al. Psychiatric Services 1995 46(10):1049-54).
In contrast, a surgically implantable preparation can last for many months, providing patients with symptomatic improvement and possibly delayed disease progression for periods of time never before possible. Additionally, in the event of unacceptable side effects, implants can be removed. This offers a degree of reversibility not presently available with depot formulations. Further, surgically implantable formulations can be employed as a safety net in combination with oral dosing to achieve adjustments as clinically indicated.
Surgically implantable drug delivery systems have been applied in contraception, drug addiction, chemotherapy and pain management. The most widely used, NORPLANT®, (Wyeth Laboratories Inc. Philadelphia, Pa.) provides 5 years of contraception using levonorgestrel in silicon tubing, allowing for steady state diffusion of active ingredient (Woutersz, T. B. Inter. J. of Fertility 1991 3(51):51-6). Silicon-based delivery systems are ideal for hormonal delivery due to picogram daily dose requirements. However, this range is not suited for antipsychotics due to slow rates of release.
Polymer based delivery systems release milligram range daily dosing required for antipsychotic medications. The polymers used in these systems were initially used in surgical applications (Kulkarni et al. Arch. Surg. 1966 93(5):839-43), but have been modified to integrate medications to form surgically implantable or injectable formulations that release drug over weeks to months. These materials are divided into two categories, namely non-erodible and bioerodible polymers.
Non-erodible polymers release drug primarily by diffusion while leaving the delivery matrix in place. Non-erodible ethylene vinyl acetate (EVA) is a widely used non-erodible material. Subcutaneous delivery of haloperidol has been demonstrated in rats up to 250 days using EVA (Kohler et al. Neuroscience Letter 1994 170(1):99-102). This preparation delivered steady state levels of haloperidol in vitro with physiologic effects on striatal dopamine receptor regulation.
Bioerodible polymers release medication by erosion of the polymer matrix and diffusion of drug through the remaining polymer matrix. Examples of bioerodible polymers include, but are not limited to, high molecular weight polymers of lactic and glycolic acids, which can be used individually or in lactide-co-glycolide copolymers (PLGA). Advantages of PLGA copolymers include low antigenicity and clearance of breakdown products (lactic and glycolic acid) through the Krebs cycle. These materials have been used in microspheres for injectable depot preparations of chlorpromazine (Gao et al. J. Microencapsul. 1998 15(1):75-83) and haloperidol (Cheng et al. J. Controlled Release 1998 55(2-3):203-12) and are now in clinical use with risperidone (http://www.alkermes.com/index news.html, Apr. 22, 1999). Microspheres are delivered as a suspension, and last approximately 2 weeks.
Various drug delivery devices comprising biodegradable polymers are disclosed generally in, for example, U.S. Pat. No. 5,665,428, U.S. Pat. No. 5,817,343, U.S. Pat. No. 5,871,778, U.S. Pat. No. 5,989,463, U.S. Pat. No. 6,004,573, U.S. Pat. No. 6,117,949, U.S. Pat. No. 6,143,314, and U.S. Pat. No. 6,201,072. These patents each contain an extensive list of possible active agents or therapeutic classes of drugs which are suggested to be deliverable via the drug delivery device.
In addition, U.S. Pat. No. 4,883,666 teaches encapsulation of a compound for treatment of ischemic, metabolic, congenital or degenerative disorders of the central or peripheral nervous system within an implantable biocompatible polymeric device. At col. 13, lines 51-59, it is taught that polymer implants with antipsychotics can be used to treat schizophrenia. Polymer implants used in the examples of the '666 patent all comprised the non-erodible polymer ethylene vinyl acetate (EVA) and dopamine. Further, coating of the implant with a layer of EVA except for one or two holes was required for linear release. Use of bioerodible polymers in implants is suggested at col. 7, line 60 of this patent. However, no examples of implants comprising bioerodible polymers and specific therapeutic agents are taught.
U.S. Pat. No. 5,601,835 teaches similar formulations to those taught in U.S. Pat. No. 4,883,666. However, these formulations are implanted directly into the central nervous system. Again, no examples of implants comprising bioerodible polymers and specific therapeutic agents are taught.
As shown herein, however, not all pharmaceutical agents, and more particularly antipsychotic agents, are amenable to delivery via systems comprising bioerodible polymers.